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Abstract

Hughes-Stovin Syndrome (HSS) is a very rare clinical disorder characterized by thrombophlebitis
and multiple pulmonary and/or bronchial aneurysms. Less than 40 published cases of
HSS have been described in English medical literature so far. The exact etiology and
pathogenesis of HSS is unknown; possible causes include infections and angiodysplasia.
HSS has also been considered as a variant of Behcet's disease (BD). Patients with
HSS usually present with cough, dyspnea, fever, chest pain and haemoptysis. The management
of HSS can either be medical or surgical. Medical management includes the use of steroids
and cytotoxic agents. Cyclophosphamide, in particular, is a favored therapeutic agent
in this regard. Antibiotics have no proven role in HSS while anticoagulants and thombolytic
agents are generally contraindicated due to an increased risk of fatal hemorrhage.
However, their use may be considered with great care under special circumstances,
for instance, intracardiac thrombi or massive pulmonary embolism. For cases of massive
hemoptysis due to large pulmonary aneurysms or those with lesions confined to one
segment or one lung, lobectomy or pneumectomy can be carried out. However, surgical
risks merit serious consideration and must be discussed with the patient. Transcatheter
arterial embolization has emerged as a less invasive alternative to surgery in selected
cases of HSS. Overall, patients with HSS have a poor prognosis and aneurysmal rupture
is the leading cause of death. However, early diagnosis and timely intervention is
crucial in improving the prognosis. There is a need to clearly elucidate the genetic,
etiologic and pathologic basis for HSS in the future. Although most of the evidence
put forward to refute the role of an infectious agent in the etiology and pathogenesis
of HSS is based on negative blood and other body fluid cultures, more robust objective
assessment is needed through the use of electron microscopy or 16 sRNA studies. The
development of better therapeutic agents is also needed to address and prevent the
serious consequences arising from pulmonary arterial aneurysms seen in BD and HSS.
Also, the issue of anticoagulation in these patients is challenging and requires further
deliberation.

Disease name and synonyms

Hughes-Stovin syndrome (HSS, ORPHA228116) was named after two British physicians,
Drs. John Patterson Hughes and Peter George Ingle Stovin. They first described the
findings of the syndrome (deep venous thrombosis and segmental pulmonary artery aneurysms)
in a total of four male patients with pulmonary artery aneurysms in 1959 [1]. Two of these patients were their own while the remaining two had been described
previously in literature [2]. The syndrome has not been referred to by any other synonym in medical literature.

Definition and diagnostic criteria

HSS is a rare disorder of unknown etiology. Although the association between multiple
pulmonary artery aneurysms and venous thrombosis of the lower limbs had been reported
by Beattie and Hall in 1911, it was not until 1962 that the eponym "Hughes-Stovin
Syndrome" was formally introduced in medical literature for HSS [2].

Being an extremely rare disease, there is no formally described diagnostic criteria
or pathognomonic laboratory investigation for this syndrome. Generally, the syndrome
is characterized by the findings of thrombophlebitis and multiple pulmonary and/or
bronchial aneurysms [3]. One other syndrome, Behcet's disease (BD), is also associated with this aneurysm-thrombosis
combination.

Turkish venercologist Halushi Behcet described the constellation of hypopyon, iritis
and orogential ulcers in 1937 [4]. However, a decade earlier, Adamantiades had reported the disease as well. Although
this gave birth to the eponym Adamantiades-Behcet's disease [5-7], the syndrome continues to be widely referred to as BD in medical literature. The
acronym MAGIC describes the features of "Mouth And Genital ulcers with Inflamed Cartilage"
seen in BD [7].

Therefore, if a patient presents with this set of findings (aneurysms and thrombosis)
and the clinician is able to rule out other causes, then the patient either has HSS
or BD. However, BD can be ruled out if its other distinctive features are absent in
the patient. This is how HSS has been diagnosed in the majority of the case reports
in literature.

Epidemiology

HSS is an exceedingly rare disorder with less than 40 published cases in English medical
literature. For this reason, its population-based incidence can't be determined. It
usually affects the young adult population bracket (reported cases ranged in age from
12 to 48 years) and holds a strong predilection for the male gender [8-10]. HSS does not appear to have preponderance for any geographic location. Cases of
HSS have been reported from diverse geographical areas including North America, Europe,
Africa and Asia [11-14]. None of the reports have mentioned consanguineous marriages in the parents of the
patients suffering from HSS. Thus, the genetic basis and familial predisposition of
HSS remains nebulous.

Clinical description

About 25% of patients with HSS develop thromboembolism, arterial aneurysms and vascular
occlusions. The distribution of the vascular component of the syndrome is as follows:
arterial (7%), venous (25%) or both (68%) [15]. The clinical paradigm of HSS can be divided into three phases [3,10]:

a. Symptoms of thrombophlebitis

b. Formation of large pulmonary and/or bronchial aneurysms

c. Aneurysmal rupture leading to massive hemoptysis and death

These stages usually evolve successively. The first and second phases have to be present
for the diagnosis of HSS while the third phase is the usual ultimate outcome for untreated
patients. The typical presenting features of HSS are related to the presence of the
pulmonary aneurysms and peripheral venous thrombosis. These signs and symptoms are
listed in figure 1[8,16-18]. Patients can have seizures, diplopia and cephalalgia secondary to raised intracranial
pressure consequent to cerebral venous sinus thrombosis [1,19]. The raised intracranial pressure also accounts for the papilledema of the optic
disc observed in some patients with HSS [20].

Aneurysms observed in HSS maybe single, multiple, unilateral or bilateral [15]. These aneurysms generally involve the pulmonary and bronchial arteries but can also
occur anywhere in systemic circulation. For example, Herb et al have reported HSS
in a patient who had an aneurysm of the left hepatic artery [21]. Similarly, aneurysms in the iliac artery have also been described [20]. The low-pressure aneurysms are usually benign with a minimal risk for vessel dissection
or rupture [22]. Even in the cases of large dilatations with diameters up to 16 cm, this risk remains
low as long as the vascular pressures remain within control. On the other hand, high
pressure aneurysms are associated with serious morbidity and mortality [23].

Recurrent phlebitis frequently involves the large vessels resulting in thromboembolism,
with even reports of thrombosis of the vena cava, cardiac chambers, jugular vein,
iliac vein, femoral vein and dural sinuses [8,10,16,19,24-27]. Patients with thrombosis in the vena cava may have engorged abdominal superficial
veins [26].

Etiology and pathogenesis

The exact etiology and pathogenesis of HSS is currently unknown. Several proposed
theories have attempted to explain the manifestations of this rare entity [16,28]. The current consensus is that vasculitis is the primary pathologic process underlying
HSS [8].

1. Infections

Septic embolisms and abscesses have been proposed as the cause of pulmonary aneurysms
by some authorities [3,29-31]. In support of this theory, pulmonary aneurysms have been preceded by infections
in some cases, including scrotal abscesses [1,29], epididymitis [2] and oophoritis [32]. Venous thrombosis can also be considered to arise as a consequence of septic emboli,
bacterial toxins or hyperergic reactions [33].

However, infectious agents, as an etiology for HSS, have generally received less attention
due to two reasons. Firstly, various antibiotic regimens that have been tried in the
treatment of HSS have proven ineffective. Secondly, there has been a lack of positive
blood cultures in the evaluation of patients with HSS [1-3,11,29,31,32,34,35]. Cultures of other body fluids in patients have also been found to be sterile [2]. Nevertheless, the possibility of undetected organisms of low-grade virulence has
been speculated [12]. According to the initial hypothesis [1], pulmonary artery aneurysms may develop from a degenerative defect in the bronchial
arteries or may even be mycotic in origin resulting from emboli infected with low-grade
virulence organisms. However, subsequent studies have failed to find such comparable
defects in the bronchial arteries.

For BD, the following infectious agents have been implicated in the pathogenesis but
never conclusively proven: Hepatitis A, B, C, E viruses, Herpes Simplex Virus (HSV),
Parvovirus B19, Helicobacter pylori, Chlamydia pneumoniae, Streptococcus sanguis, Streptococcus mitis, Streptococcus salivarius and Saccharomyces cerevisiae [36]. The details for these agents in the pathogenesis of BD have been given in table 1. Interestingly, in support of the infectious etiology of BD, it has been suggested
that proximity to the Silk Road and interactive trade activities may have provided
the necessary bridge for the extension of the disease between the Mediterranean and
the East [5].

2. Angiodysplasia

Angiodysplasia of bronchial arteries is another debatable hypothesis to account for
the vascular changes [16,28,37]. Hughes and Stovin suggested that the structural changes in the bronchial arteries
impaired the provision of adequate nutrition to the pulmonary arteries through the
vasa vasorum. In turn, these events led to inflammation, damage to the elastic tissue
and creation of arterial aneurysms [21]. Conversely, it has been suggested that the occlusion of the pulmonary arteries causes
increased flow and pressure in the bronchial arteries which predisposes to the formation
of bronchial artery aneurysms [21].

3. Possible manifestation of Behcet's Syndrome

Some authors have suggested that HSS may actually be a partially manifested BD owing
to their similar findings instead of a novel syndrome [16,19,38,39]. In fact, HSS and BD are the only vasculitides associated with the development of
pulmonary artery aneurysms [4,40,41]. HSS has been variably described as "the cardiovascular manifestation of Behcet's
disease" [14], "incomplete Behcet's" [19] and "a rare case of Behcet's disease" [42] in literature.

4. Mechanism of Thrombosis

The pathogenesis of thrombosis remains unclear in both HSS and BD. Thrombophilia is
not believed to be a major contributory factor to the development of thrombosis in
these patients [15]. Possible mechanisms to explain the prothrombotic nature of BD in literature include:
progressive decline in endothelial progenitor cells, direct endothelial injury, aberrant
fibrinogenolysis and platelet activity, abnormal levels and expression of thrombomodulin,
adrenomodulin and vascular endothelial growth factor (VEGF), E-selectin activation
and variable nitric oxide levels [5,36]. Some reports have also described the contribution of prothrombin gene mutations
and aberrant protein C levels and activity in the thrombotic events of BD [43,44].

The presence of hyperhomocyteinemia independently adds to the risk of venous thromboembolism
in HSS. Homocysteine causes thrombosis through multiple mechanisms including the activation
of platelets, increased thrombin formation, impairment of fibrinolysis and endothelial
dysfunction through lipid peroxidation and endothelial injury [45].

An important detail that merits consideration here is that the clot in the pulmonary
arteries in HSS or BD arises mostly due to the arterial vasculitis rather than venous
thromboembolism, especially in patients without deep venous thrombosis. Also, the
thrombin in the lower extremities is tightly adherent to the inflamed veins in BD
and HSS patients [12,19,37]. Balci et al [20] have reported the case of a patient in whom the pulmonary emboli recurred despite
the placement of the Greenfield filter. Although the event can simply be attributed
to the failure of the Greenfield filter, the possibility of the in situ formation
of the pulmonary embolus as a separate entity from the deep venous thrombus can't
be ignored.

5. Extrapolation of the pathologic model for Behcet's disease

As mentioned earlier, although the exact pathologic basis for HSS is unclear, it may
be similar to the model for BD as the two conditions share many features. Interplay
of multiple factors such as genetic, environmental, immunological and endothelial
is most likely to be involved in the pathogenesis of BD [36].

Strictly speaking, BD is not considered an autoimmune disease [36] because of the following reasons: a) B-cell hyper-reactivity not noted, b) female
predominance not reported across the board, c) absence of Sjogren syndrome in patients
with BD. However, immunologic mechanisms, different from those in other autoimmune
diseases, are believed to be involved in the pathogenesis of BD. A growing body of
evidence is suggestive of the active role of T-cell mediated immune mechanisms and
responses in BD. In particular, γδ+T-cells are thought to be involved in BD and their
stimulation results from microbial antigens produced by the oral flora [36]. The exact role and interactions of CD4+ T-cells and its subsets, CD8+ T-cells, double
negative T-cells and other antigen presenting cells (APCs) in BD are also being investigated.
In addition, neutrophil hyperactivation, a key component of inflammatory vasculitis
seen in BD, occurs secondary to the release of the battery of cytokines from the APCs
and T-cells. Neutrophils exhibit increased generation of reactive oxygen species (ROS),
phagocytic capacity and cytokine production as well [5,36].

The main players of the cytokine axis active in BD include interferon-γ, IL-1b, IL-6,
IL-8, IL-12, IL-18 and TNF-α [5,36]. A role of autoantibodies in the expression and manifestations of BD has also been
proposed (table 2) [5,36].

6. Bridge to immunogenetics

Classically and most convincingly, the association of BD has been described with the
human leukocyte antigen (HLA) B51 in literature. In a recent met-analysis/systematic
review comprising 4,800 cases and 16,289 controls, the pooled odd's ratio for the
susceptibility to BD associated with HLA-B51/B5 carriage was 5.78 (95% CI: 5.00 -
6.67). The population-attributable risk (PAR) of HLA-B51/B5 in relation to BD was
32% (Northern/Eastern Europe) to 52% (Southern Europe). This study also showed that
the random-effects pooled prevalence for HLA-B51/B5 was 57.2% (95% CI: 53.4 - 60.9%)
in cases of BD versus 18.1% (95% CI: 16.1 - 20.3%) in controls [46]. It is speculated that HLA-B51 forms an integral part of an immunologic axis in patients
with BD that interacts with cross-reacting self-antigens and immunoglobulin-like receptors
on immune cells of the body [36]. However, it is still unclear whether the strong association of BD with HLA-B51/B5
is representative of a true causal association or demonstrates linkage disequilibrium
with another gene that is operational in BD [46].

In addition to the strong association of BD with alleles of the major histocomptability
complex (MHC), recent studies have also highlighted the polygenic status of BD and
investigated the role of additional genes in BD including, but not limited to MIC,
MEFV, TNF, HSP etc [5,36].

In contrast, out of all the literature reviewed, only one report described the testing
of a patient with HSS [13] for HLA-B51. The latter was found positive in this patient. However, the trend obviously
needs to be confirmed in other patients before deriving any conclusions. Also, it
is not known whether patients in other reports on HSS were tested for HLA-B51 or not
as no specific comment regarding such testing was made or alluded to in those reports.

Diagnostic considerations

The diagnosis of HSS can be difficult owing to a non-specific set of findings.

2. Bronchoscopy

Bronchoscopy is often done in HSS patients who present with hemoptysis. In patients
with bronchial artery aneurysms, fibre bronchoscopy can show pulsatile tumor(s) with
fibrinoid onlayers and/or ectatic vessels [21] or bronchial obstruction caused by submucosal mass [38].

3. Ventilation-perfusion (V-Q) scan

Patients with HSS can develop pulmonary embolism. The formation of these emboli has
been attributed to the inflammatory response of the endothelial cells lining the vessels
[26]. The V-Q scan in such patients shows area(s) with ventilation-perfusion mismatch.

4. Doppler ultrasound of extremities

Peripheral venous thrombosis is an important part of HSS. Color Doppler examination
of the extremities should, therefore, be undertaken to evaluate the presence of deep
venous thrombosis on the basis of reasonable clinical suspicion.

5. Radiological diagnosis

a. Chest roentograms

Figure 2.X-ray of the chest showing an infiltrate in the lower lobe of the right lung. Reproduced with permission from Al-Jahdali H [15]

Figure 3.CT scan of the chest showing ill defined infiltrate in lower lobe of the right lung. Reproduced with permission from Al-Jahdali H [15].

b. Conventional angiography

Traditionally, conventional angiography (figure 4) has been regarded as a gold standard for the diagnosis of pulmonary artery aneurysms.
It also aids in assessment of angiodysplastic bronchial arteries in HSS. The characteristic
picture seen is aneurysmal formation proximal to the occluded segments while distal
to the interruption, signs of hypoperfusion are observed [48]. However, it should be noted that selective pulmonary angiography can be hazardous
as it carries the risk of aneurysm rupture [17].

c. Helical computed tomography

However, it may not be possible to perform angiography in all patients; especially
in patients with thromboses in the vena cava which limit the passage of the catheter
[26]. In such cases, other non-invasive modalities such as helical computed tomography
(CT) may demonstrate high quality vascular images with minimal amount of contrast
material used (figure 5). In fact, multi-detector row helical CT angiography now offers more precise visualization
of large systemic arteries than does conventional angiography. As such, it can be
regarded as an emerging and effective standard in the diagnosis of pulmonary artery
aneurysms because of its non-invasive nature, ease of performance and increasing availability.
Furthermore, Ketchum et al showed that 3D volume rendering analysis can detect morphologically
abnormal, tortuous branches of bronchial arteries even before aneurysm formation [12,49]. Mahlo et al [17] and Herb et al [21] recorded distorted and dilated bronchial arteries with convoluted small branches
when they performed digital subtraction angiography of the bronchial arteries.

d. Magnetic resonance angiography

Magnetic resonance angiography (MRA) is relatively less sensitive than helical CT
for picking up small aneurysms [20,26,47,49].

6. Histological diagnosis

Classic histopathologic findings of HSS [1,2] include diffuse dilatation and partial occlusion of the aneurysmal arteries, perivascular
infiltration that is predominantly lympho-monocytic and diffuse proliferative sclerosis.
The elastic and muscular fibers become annihilated whereas tunica media is completely
filled with lymphocytes, plasma cells and foam cells in the affected vessels. The
perivascular infiltrate extends into the adventia and into the overlying thrombus.
Macrophages containing hemosiderin may also be observed. In the pulmonary veins, fibrosis
and muscular medial thickening is seen. However, Durieux et al [37] described a dense neutrophilic infiltrate in the walls of the vessels in HSS. On
the other hand, Meireles et al [35] reported the histologic findings of HSS in a patient's necropsy as medial hypertrophy,
intimal fibrosis with marked eosinophilic infiltrates.

In comparison, the histology of vascular lesions in BD is characterized by a triad
of "neutrophilic infiltration", "endothelial cell swelling" and "fibrinoid necrosis"
[5]. Similarly, neutrophils establish an early presence in the mucocutaneous and ocular
lesions of BD [5].

The pulmonary arteries showed widespread lesions of Regardless of the modality used,
a complete visualization of prominent bronchial arteries and pathologic enhancement
of pulmonary thromboembolism should alert physicians to the suspicion of pulmonary
vasculitis. A timely diagnosis and intervention is imperative to prevent potentially
life-threatening massive hemorrhage due to pulmonary aneurysms [12].

Differential diagnosis

Amongst the causes for pulmonary artery aneurysm (table 3) [50], there are two idiopathic, albeit similar, syndromes that are associated with thrombosis:
BD and HSS. There exists a significant overlap between the clinical, radiological
and histopathological findings of HSS and BD (table 4). Specifically, pulmonary involvement is often indistinguishable between the two
entities. However, whether the two conditions are identical is open to both debate
and speculation as the exact pathophysiology of both syndromes remains unclear.

The target populations as well as the pulmonary manifestations in BD appear to be
similar to that in HSS (table 4). Also, both diseases are characterized histologically by the destruction of the
vessel walls of pulmonary vasculature along with perivascular infiltration [37,50]. BD primarily affects young adults, especially males [40,41,51]. However, this gender distribution is not universal. There are also studies which
have shown a female preponderance [52,53]. This is in contrast to HSS where the majority of the cases (>80 - 90%) have been
seen in male population. Although BD is found all over the world, certain regions
like Far East, the Mediterranean (the ancient "Silk Road") and the Middle East have
reported higher rates of prevalence [36,40,41,51,54]. BD has been known to occur more commonly in geographic areas that fall between latitudes
30 and 45 degrees north [7]. The incidence of BD in different regions is as follows: North America and Europe
- 0.38 - 7.5/100,000 and Turkey - upto 42/100,000 [36].

Findings unique to BD are recurrent genital ulceration, eye lesions, skin lesions,
iritis, arthralgia and a positive pathergy test [40,55,56] and this helps in distinguishing the two entities. For the clinical diagnosis of
BD, the patient must have recurrent oral ulceration with atleast two of the following
clinical manifestations: recurrent genital ulceration, skin lesions, eye lesions or
a positive pathergy test [57]. The pathergy test is performed by taking a sterile 20 - 22 gauge needle and obliquely
piercing the skin to a depth of 5 mm. If the site develops an erythematous papule
after 48 hours, the test is positive [5].

It is believed that the aneurysms seen in BD arise either due to the process of obliterative
endarteritis of the vasa vasorum or they are pseudo-aneurysms characterized by edematous
vessel walls. The latter are usually formed after perforation [38].

Management

Owing to the lack of controlled trials, there are no standard treatment guidelines
for the management of HSS. As BD and HSS share certain clinical characteristics and
manifestations, the management of HSS can be tailored along the lines of BD [19]. Despite this, it should be noted that the European League Against Rheumatism (EULAR)
has acknowledged the need for properly designed and robust prospective studies for
improving management strategies even for BD [58,59]. In this section, relevant EULAR recommendations with regards to the management of
BD disease have been referred to, especially with regards to vascular disease.

1. Medical management

a. Immunosuppressive therapy

Most commonly, immunosuppressive therapy involving a combination regimen of glucocorticoids
and cyclophosphamide has been employed as a first line medical management in the treatment
of HSS, although its effectiveness remains to be fully established [8,40]. The steroids are usually administered as pulse IV therapy followed by oral steroids
usually with subsequent taper [15,19,38,45]. Depending upon the clinical response, steroids can be discontinued but cyclophosphamide
is usually given for at least one year after complete remission [4]. One described regimen for the treatment of arterial aneurysms is monthly pulses
of cyclophosphamide (1 gram) plus prednisolone (1 mg/kg/day). The latter is then tapered
over the course of several months to a dose less than 30 mg/day [60].

Immunosuppression has the potential to stabilize small aneurysms in the pulmonary
vasculature [8], and in some cases can even make them regress [27]. Other agents that have been variably used in the treatment of HSS include colcichine,
cyclosporine and azathioprine [8,15,38]. However, despite the favorable response seen in some cases, the caveat that needs
to be remembered is that immunosuppressive therapy may not always be helpful in the
cessation of disease progression especially if the disease has already evolved to
an advanced stage [61].

EULAR recommends the use of steroids, azathioprine, cyclophosphamide or cyclosporine
A for the management of acute deep vein thrombosis of BD while cyclophosphamide and
corticosteroids have been recommended for pulmonary and peripheral arterial aneurysms
in BD [58]. For pulmonary aneurysms, EULAR has recommended the continued use of cyclophosphamide
for two years followed by azathioprine [58]. Cyclosporine A, being neurotoxic, should not be used in patients with neurological
manifestations of BD [58].

b. Antibiotics

c. Anticoagulants and thrombolytic agents

Anticoagulants and thombolytic agents are generally considered contraindicated due
to an increased risk of fatal hemorrhage, even though they confer a beneficial effect
in an embolic state [37]. Some patients with HSS already have hemoptysis at initial presentation; making these
agents an unsafe therapeutic option. This places physicians on the horns of a dilemma
because of the pro-thrombotic nature of the syndrome and the occurrence of potentially
life-threatening events such as intracardiac thrombi or pulmonary embolism. Therefore,
anticoagulation may be employed with great vigilance in a few carefully evaluated
circumstances where the benefits are believed to significantly outweigh the risks.
Kim et al successfully used anticoagulation in a patient with HSS, hyperhomocysteinemia
and intracardiac thrombi employing warfarin with enoxaparin as a bridge [45]. Tsai et al have recommended that in patients with pulmonary embolism and HSS, anticoagulation
should be used very judiciously. This is only in patients with embolisms in the main
pulmonary artery that lead to life-threatening clinical deterioration and hemodynamic
instability [26]. Anticoagulation maybe used to prevent or treat deep vein thrombosis after the pulmonary
artery aneurysms have been surgically resected [15] or after adequate immunosuppressive treatment has been given [40]. This is usually achieved by starting the patient on intravenous or subcutaneous
heparin and then shifting to oral warfarin therapy. However, the caveat here is that
patients may still develop thrombosis despite adequate anticoagulation [38]. Another point to consider is the possible role of deep venous thrombi in aneurysm
formation. By that logic, long term anticoagulation may have the potential to prevent
further aneurysm formation by targeting this particular mechanism [62].

The issue of anticoagulation in patients with HSS and BD is obviously complex and
requires focused studies before any definite recommendation can be made. EULAR has
stressed the need for controlled trials to evaluate the utility of anticoagulation
in patients with BD. The use of anticoagulants and antifibrinolytic agents in BD is
not currently recommended by EULAR [58].

d. Antiplatelet agents

In the absence of extensive thrombi, some authors have suggested the use of antiplatelet
agents such as low dose aspirin in patients [63,64]. However, EULAR doesn't currently recommend the use of antiplatelet agents in BD
[58].

e. Ventilator support

Patients presenting with severe hemoptysis may require initiation of mechanical ventilator
support [65].

f. Surgical consultation

Along with the initiation of medical management, an urgent consultation should be
given to the cardiothoracic surgery team, especially if the patient presents with
severe or recalcitrant hemoptysis [26].

2. Surgical management

For the cases of massive hemoptysis due to large pulmonary aneurysms or those with
lesions confined to one segment or one lung, lobectomy or pneumectomy can be carried
out to remove the aneurysms based on the data from published case reports. Kindermann
et al have described the resection of pulmonary artery aneurysm with the reconstruction
of the arterial segment using a saphenous vein grafts [66]. Durieux et al [37] used surgical intervention for three cases of HSS who had isolated pulmonary aneurysms
and none of them showed any signs of recurrence on subsequent follow ups. However,
this is not the case for most patients of HSS where bilateral, extensive pulmonary
aneurysms limit the role of surgery as the frontline treatment modality. Furthermore,
high operative morbidity and mortality associated with surgery is another consideration
that must be discussed with patients [1,2,66,67]. Additionally, after surgery, there is a 25% risk of recurrence of aneurysms at the
site of anastomosis [68].

For BD, Alexoudi et al have recommended that surgery be considered as a treatment
of choice for vascular involvement in the following circumstances: expanding aneurysm,
acute rupture and severe ischemia [69]. However, surgeons should be aware of the possibility of the formation of pseudoaneurysms
(if arterial involvement) and false anastomotic aneurysms (if venous involvement)
after surgical intervention. The pre-operative use of doxycycline has been recommended
because of its potential role in off-setting these deleterious post-operative events
[69].

3. Transcatheter arterial embolization

For patients who are not suitable candidates for aggressive surgical intervention,
transcatheter arterial embolization, being a less invasive procedure, offers a suitable
and effective alternative in HSS [8]. Furthermore, since aneurysms in HSS are usually bilateral and multifocal at the
time of diagnosis, embolization is a preferred modality in such patients [8]. Arterial embolization is also an acceptable therapeutic option in patients with
severe or recurrent hemoptysis [21]. Authors have performed embolization with several agents including steel coils, ethibloc
and an epoxy, isobutyl cyanoacrylate [8]. Associated complications of arterial embolization include arteriovenous fistulae,
pulmonary infarction, abscess formation, oesophageal necrosis, bronchial necrosis,
and spinal ischemia [70,71]. Rarely, the patients may require repeat embolization because the arterial lesions
may become recanalized or revascularized [21]. Balloon venoplasty may be used in patients with vena caval thrombosis. However,
it is only safe to perform this procedure in the early stages [72].

Prognosis

Aneurysms of arterial origin portend a poorer prognostication than venular aneurysms
[15]. In particular, pulmonary artery aneurysms have a poor prognosis. Hemoptysis can
arise from three mechanisms in patients:

1. Aneurysmal rupture; it is the leading cause of death in patients of HSS. The erosion
of the ruptured aneurysm into a bronchus leads to hemoptysis [73].

3. Bronchial artery hypertrophy secondary to ischemia that, in turn, has been attributed
to the pulmonary artery occlusion [21]. Mahlo et al. speculated that the cause of death in HSS could be due to the rupture
of angiodysplastic bronchial arteries rather than rupture of aneurysmal pulmonary
arteries [17].

Early diagnosis and timely intervention is, therefore, crucial in improving the prognosis
of patients with HSS. Appropriate treatment, if instituted promptly and early in the
course of the disease, has the potential to induce remission [4,40,47,54,74].

Future directions

There is a lack of clear diagnostic criteria and management guidelines for HSS. The
disease is clearly a rare but grave clinical entity and has not been extensively studied
so far. Most of the data on HSS is in the form of sporadic case reports. Establishing
diagnostic criteria and formulating management guidelines for HSS is imperative to
standardize the quality of care delivered and to improve prognosis across the different
geographic regions of the world since HSS is associated with significant morbidity
and mortality. There is also a need to better elucidate the genetic basis and familial
preponderance, if any, of HSS. As with any genetic disease, knowledge of the latter
will be helpful to clinicians in the provision of pre-conception genetic counseling
to patients with HSS.

Future investigations should include human leukocyte antigen (HLA) typing in patients
to compare and contrast the genetic basis of HSS with BD. Although it should be acknowledged
that HSS and BD share many clinical, radiological and histological features, the suggestion
that they are, in essence, the same disease can neither be currently accepted nor
categorically refuted because the pathologic, genetic and etiologic basis of both
conditions has not been clearly unraveled. These aspects have been highlighted for
focused research in the future. Unless these arenas are elucidated, the "pathogenic
kinship" between the two conditions remains obscure [18] and should be examined with scientific skepticism and perspicacity. Although most
of the evidence put forward to refute the role of an infectious agent in the etiology
and pathogenesis of HSS is based on negative blood and other body fluid cultures,
more robust objective assessment is clearly needed through the use of electron microscopy
or 16 sRNA studies. Finally, the development of better therapeutic agents is needed
to address and prevent the serious consequences arising from pulmonary arterial aneurysms
seen in BD and HSS. Also, the issue of anticoagulation in these patients is challenging
and requires further deliberation.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

UK performed the literature search, interpreted the data and drafted the manuscript.
TS conceived the project, performed the literature search, interpreted the data, drafted
the manuscript and critically revised it. All authors have read and approved the final
manuscript.

Acknowledgements

We are greatly indebted to the reviewers for their valuable suggestions and critique.